FDA’s final guidance retains much of the contents of the draft version and reflects changes in FDA’s thinking about the breakthrough therapy program based on its review of approximately 186 requests for designation to date, 48 of which have been granted. The guidance also provides new details related to accelerated approval.

Overarching themes in the final version of the guidance include explicit references to flexibility related to rare disease; the incorporation of the benefit-risk paradigm, which takes into account the severity of the disease or condition; and clearer statements that products “prevent[ing] a serious condition or reduc[ing] the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease” should be eligible for these expedited programs.

Breakthrough therapy designations

FDA’s changes to the breakthrough therapy designation portion of the guidance amount to a fine-tuning of the program rather than a major overhaul. The following are some of the important clarifications made:

A grant of breakthrough therapy designation does not guarantee approval.

A drug that has its breakthrough therapy designation rescinded “may still have sufficient evidence after completion of the drug development program to support marketing approval.”

A suggestion by the Agency that a sponsor consider submitting a request for breakthrough therapy designation is “advisory and should not be interpreted as guaranteeing breakthrough designation.”

Although demonstrating substantial improvement over existing therapies is traditionally done by analyzing preliminary comparative data against available therapies, other types of clinical data may also be persuasive, including data collected in single-arm studies comparing a new treatment with well-documented historical experience. Examples of single-arm trials that may be persuasive include:

Study data showing that a new drug significantly increases lung function in cases where lung function decline is a major manifestation of a disease, and where there is no available therapy that increases lung function; and

Data demonstrating that a cancer drug substantially increases overall response rate compared with historical controls, with consideration of duration of the response.

The definition of “available therapy” has been modified to include a drug that is “granted accelerated approval because of restricted distribution and the study population for the new drug under development is eligible to receive the approved drug under the restricted distribution program.”

The final guidance also elucidates the evidence needed to demonstrate that a pharmacodynamic (PD) biomarker is a clinically significant endpoint. This includes the extent of understanding of the disease pathophysiology; whether the biomarker is on a causal pathway of the disease process; and the time course of the drug’s effect on the biomarker (i.e., a showing that the biomarker can be measured earlier than a surrogate endpoint).

An explicit reference to a rolling review feature has been added, although this was implied in the draft guidance.

Accelerated approval

The accelerated approval section of the guidance also makes several clarifications and expresses FDA’s priorities. The final guidance:

Restates the Agency’s “longstanding commitment to regulatory flexibility regarding the evidence required to support product approval for the treatment of serious or life-threatening diseases with limited therapeutic options.”

Stresses that manufacturers seeking approval for drugs that may be approved via the accelerated pathway should be prepared for a rapid pace of drug development (e.g., manufacturing and development of companion diagnostics).

Slightly modifies the definition of intermediate clinical endpoint (“ICE”) to mean “a therapeutic effect that can be measured earlier than an effect on [irreversible morbidity or mortality (“IMM”)] and is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit.”

States that an important consideration in the use of ICEs is whether the demonstrated therapeutic effect alone would be a basis for traditional approval. Approvals for products for serious conditions based on clinical endpoints other than IMM will usually be considered under traditional approval procedures.

Provides additional examples of surrogate endpoints and ICEs that can be used to support an accelerated approval.

Provides additional clarity related to the due diligence requirement for confirmatory trials for drugs approved via the accelerated approval pathway.